Diazoalkanes are important compounds in organic synthesis and are commonly used as intermediates or reactants in reactions such as the etherification of NH bonds, OH bonds or acid bonds, or during syntheses of heterocyclic compounds. They are also used in addition and insertion reactions under mild conditions.
Diazomethane is a highly reactive gas with a wide range of uses in chemical syntheses. It is commonly used as a methylating agent for a wide variety of compounds, as well as being used for ring expansion or chain extension of ketones and for the conversion of ketones to epoxides. It is also commonly used in cycloaddition reactions with olefins to produce cyclopropyl or nitrogen-containing heterocyclic rings. Diazomethane also has pharmaceutical implications, for example in the formation of viral protease inhibitors including those to combat HIV, especially where an addition of a carbon atom is required without compromising the chirality of the amino acid or affecting the rest of the molecule.
Diazomethane is a hazardous reagent. It is both a carcinogen and an allergen, as well as being highly poisonous. Further, it is highly explosive, which poses a problem during its synthesis.
The synthesis of diazomethane from N-alkyl-N-nitroso compounds is well-known in the art and often involves the addition of a base. A commonly used N-alkyl-N-nitroso compound is N-nitroso-β-methylaminoisobutyl methyl ketone (“Liquizald”), the preparation of which is also known in the art. Liquizald is usually made from mesityl oxide, which is then reacted with methylamine to create an intermediate amine. This intermediate amine is then treated with acid and a source of nitrite to form Liquizald. Liquizald has various advantages over other commonly used N-alkyl-N-nitroso compounds, such as Diazald, which include stability, cost and availability.
The preparation of Liquizald from mesityl oxide and its use for producing diazomethane was first described by Jones and Kenner (Journal of the Chemical Society, 1933, p 363-368). The method uses monobasic hydrochloric acid to acidify an intermediate amine, although the quantity of acid used is not specified. After acidification, the solution is extracted with diethyl ether to remove residual mesityl oxide and the Liquizald product is distilled. This distillation is potentially hazardous as the product is reported to be unstable when heated.
Diazomethane was generated from the purified Liquizald by reacting a solution of Liquizald in diethyl ether with various sodium alkoxides generated from ethanol, isopropanol, n-propanol, sec-butyl alcohol, methylpropylcarbinol and tertiary butyl alcohol and heating the solution to recover an ethereal solution of diazomethane. Yields ranged from 0% (using the sodium salt of tert-butanol) to 83.5% (using the sodium salt of isopropanol).
In a subsequent publication, Adamson and Kenner (Journal of the Chemical Society, 1937, p1551-1556) describe an improved method for generating Liquizald in which monobasic acetic acid is used. This method formed the basis of an Organic Synthesis publication (Organic Synthesis, Coll Vol. 3 p. 244 (1955); Vol. 25, p. 28 (1945)). The method generated Liquizald with a yield of 70-80% based on mesityl oxide but required back extraction using diethyl ether to achieve this yield.
The generation of diazomethane was described using sodium isopropoxide in isopropanol/ether at 70-75° C., giving a diazomethane yield of 45-60%. A second method is described using sodium cyclohexoxide in cyclohexanol/ether at 50-55° C., which gave a diazomethane yield of 77-84%. A method for generating gaseous diazomethane is also described, by reacting an anisole solution of Liquizald with sodium cyclohexoxide to give a diazomethane yield of 65%.
U.S. Pat. No. 5,817,778 describes the use of phase transfer catalysis for generating diazomethane from a N-alkyl-N-nitroso compound in an organic solvent. The phase transfer catalyst enhances the rate of reaction between a reactant in the aqueous phase and one in the organic phase. The solvent is used to prevent the detonation of the diazomethane and is co-distilled with the diazomethane so that the amount of diazomethane within the vapour produced is maintained within safe limits. However, the N-alkyl-N-nitroso compound defined in U.S. Pat. No. 5,817,778 does not include Liquizald.
WO00147869 discloses a continuous method for generating diazomethane from a N-alkyl-N-nitroso compound, with Liquizald as an exemplary N-alkyl-N-nitroso compound, in a solvent such as DMSO.
US2007/0249817 refers to the WO patent above but describes a method for removing the produced diazomethane as a gas, using reduced pressure.
U.S. Pat. No. 3,963,698 discloses the use of N-methyl-N-nitrosourea in a 1,2-dimethoxyethane and water solution, in the presence of a base, to produce diazomethane. In this reaction, 1,2-dimethoxyethane is used as a solvent and is present at a ratio to water of 5:1, thereby creating a single phase homogeneous solution.
The decomposition of Liquizald to form diazomethane is also disclosed in Helv Chim Acta (Vol 63(4), 1980, p887-891), where the use of potassium hydroxide at low temperatures in the presence of toluene is disclosed.
The importance of diazomethane as a reactant and an intermediate in many chemical reactions, as well as its toxicity and explosiveness, means that there is a need for methods that create diazomethane at high yields but also maintain the required safety standards. Safety could be increased by eliminating the need for a distillation step. Further, the use of certain organic solvents can pose environmental and waste disposal problems, so eliminating the need for such solvents would also be beneficial.
While the invention will be described in connection with certain preferred embodiments, it is not intended to limit the invention to the particular embodiments. On the contrary, it is intended to cover all alternatives, modifications and equivalent methods as may be included within the scope of the invention as defined by the appended claims.